In general, slightly water-soluble medicaments have poor oral absorbability because of their low solubility and low dissolution rate in the digestive tracts. Various methods have been investigated to improve the oral absorbability. Known examples of the methods include (a) a wet granulation method using a hydrophilic polymer, (b) a method in which the medicament is fined by grinding, (c) a method in which a solid dispersion is formed with a polymer material, (d) a method in which a soluble clathrate is formed together with cyclodextrins, (e) a method in which a surfactant is added, and the like.
The method (a) is known as a simple method in which the wettability to water of a medicament which is relatively water-insoluble can be improved to raise the dissolution rate thereof [J. Pharm. Sci., 59, 49 (1970) etc.] However, the effect is so limitative that the oral absorbability of a medicament which is quite slightly water-soluble cannot be sufficiently improved.
The method (b) is known as a method for raising the dissolution rate of a slightly water-soluble medicament by increasing the surface area thereof [Dissolution Technology, the Industrial Pharmaceutical Technology Section of the Academy of Pharmaceutical Science, p. 108 (1974) etc.] However, the size to be fined by grinding is so limitative that there are some problems that particles are aggregated or hardly wettable and the like when the finely ground medicaments are dispersed in water. Although a combination of the method (a) and the method (b) is frequently used, this combination is still insufficient for improving the oral absorbability of a quite slightly water-soluble medicament.
When a solid dispersion is formed in the absence of water in accordance with the method (c) (Japanese Published Unexamined Patent Application No. 110612/81 etc.), the solubility of a slightly water-soluble medicament is transiently increased upon the dispersion of the solid dispersion in water. However, there is a problem that the medicament is crystallized after a definite period of time and thus the solubility thereof is decreased. In addition, it is known that the stability of a solid dispersion obtained by the method (c) is sometimes decreased when stored under highly humid conditions. Moreover, there is a further problem that an organic solvent such as a halogenated solvent which is problematic in safety is necessary in many cases in the step of preparing the solid dispersion of the medicament.
In the method (d), there are some medicaments which do not form a clathrate, because the formation of a clathrate depends on the structure of a medicament [Pharmaceutical Technology, 15, 24–38 (1991) etc.]
In the method (e), a large amount of a surfactant is necessary to improve the solubility of a quite slightly water-soluble medicament. However, since many surfactants are in the form of liquid or wax, they sometimes disturb the preparation of a solid product. Even if the solubility is improved, the oral absorbability is sometimes decreased by micellation due to a surfactant depending on the properties of the medicament [Chemical & Pharmaceutical Bulletin, 18(8), 1563 (1970) etc.]
As a method for improving the bioavailability of a steroid medicament which is less than 100 to 200 ng/ml, U.S. Pat. No. 4,684,636 discloses a method wherein beads made of a saccharide or the like are coated with an aqueous suspension containing the steroid medicament, a binder and an optional wetting agent and then are put into capsules. In this method, however, it is somewhat troublesome to produce the product and the effect is still insufficient because an area under curve (AUC) of the medicament concentration in plasma is not more than twice as large as that of a dry mixture of the medicament with an excipient free from a wetting agent.
Under these circumstances, the composition which is easily used and has high effects, in which a slightly water-soluble component has improved solubility or oral absorbability, has been required.